Corneal toxicity with belantamab mafodotin: Multi‐institutional <scp>real‐life</scp> experience
Authors: Meera Mohan, Lisa E. Rein, Nishanth Thalambedu, Yetunde Ogunsesan, Munawwar Hussain, Jaskirat Sethi, Fatima Khan, Sravani Gundarlapalli, Lakshmi Yarlagadda, Binod Dhakal, Mary Price, Megan Shirey, David B. Warner, Sharmilan Thanendrarajan, Siegfried Janz, Sabarinath Venniyil Radhakrishnan, Samer Al Hadidi, Aniko Szabo, Anita D'Souza, Maurizio Zangari, Frits van Rhee, Saurabh Chhabra, Carolina Schinke
Journal: American Journal of Hematology (2022)

To the Editor: Since the regulatory approval of monoclonal antibody targeting CD38 antigen in an upfront setting, triple class refractory1 multiple myeloma (MM) is increasingly encountered at an early stage of the disease2 and patients who fall in this category are in dire need of novel therapeutic options. Belantamab mafodotin is a first-in-class anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to microtubule-disrupting agent monomethyl auristatin F (MMAF) (mafodotin)3 that was approved by the FDA in 2020 for relapsed, triple class refractory MM. Although belantamab has significant single agent efficacy in heavily pretreated MM patients, its use is characterized by keratopathy in up to 70% of patients. This particular and reversible side effect is caused by corneal microcyst-like epithelial changes following internalization of belantamab leading to apoptosis of epithelial cells, which are eventually replaced with new epithelial cells.4 Studies have described that keratopathy has led to significant dose reductions (23%) and dose delays (47%)5 with unknown consequences on treatment outcome. The subjective symptoms of keratopathy, including blurred and reduced vision can result in impaired life quality and has led some patients to come off therapy despite good response. In an effort to summarize the impact of keratopathy during belantamab therapy, we report our multi-institutional, real-world data of belantamab in 56 patients with relapsed refractory multiple myeloma (RRMM). Fifty-six patients with RRMM from two academic institutions (Medical College of Wisconsin, University of Arkansas for Medical Sciences) who received at least one cycle of belantamab were included in the analysis. Risk was assessed according to revised ISS criteria,6 and positron emission tomography-computerized tomography (PET-CT) defined focal lesions (FL) ≥3,7 as previously described. High-risk cytogenetics were defined as presence of translocations t(4,14), t(14,16) or t(14,20), 1q21 abnormalities ≥3 copies or del 17p.8, 9 All patients were enrolled in belantamab risk evaluation and mitigation strategies (REMS), underwent a baseline ophthalmologic evaluation prior to the first dose and serially before every dose with subsequent treatment modifications.10 Statistical analysis is reported in Supplemental text. The baseline characteristics of patients are shown in Table S2. The median age was 66 years with 34% (n = 19) patients being female and 20% (n = 11) Black Americans. About 96% (n = 54) of patients were triple class refractory. Among these, 59% of patients had ≥3 FL and 29% extramedullary disease by PET CT. Eighty-three percentage (n = 47) of patients had at least one autologous stem cell transplant (ASCT) and 40% (n = 22) had additional salvage ASCT for relapsed disease. The median prior lines of therapy were 5 (range 2–11). In the majority of patients belantamab was started at a dose of 2.5 mg/kg (91%, n = 51). In 5 patients, a reduced dose of 1.9 mg/kg was the initial starting dose at the treating physician's discretion. A 3-weekly dosing schedule was used in 82% (n = 46/56), whereas the reminder started with a q 4 week schedule (10/56), Table S2. The median duration of belantamab therapy was 7.7 (range 6.7-NR) months. About 27% (n = 15) of patients had already existing baseline grade 1 keratopathy prior to initiation of belantamab therapy, which is consistent with previous reports that patients with MM have an increased incidence of underlying ocular comorbidities.11 Data on follow-up ophthalmological examination were missing in eight patients, as those patients progressed after the first belantamab dose and were taken off therapy. The cumulative incidence of new or worsening keratopathy increased with longer duration of therapy (Figure 1A) and was 71.4% at 4 months (n = 40), with grade 3 keratopathy accounting for 54% (n = 26/48) of assessable patients. There were no grade 4 events and the rates of worsening keratopathy were not different between patients with and without baseline keratopathy. Among patients who developed new or worsening keratopathy the median time to event was 1.4 (range 0.7–4.8) months. By month 4 of belantamab therapy, 48% (27/56) of patients required treatment interruption due to keratopathy (Figure 1B) and as of data cut off, treatment was held in 55% (31/56) patients for keratopathy. Belantamab was subsequently restarted in 54% (17/31) of patients with 88% (15/17) of patients having a dose reduction to 1.9 mg/kg. Further, the dosing frequency was modified to every 4 and 6-weekly dose in 28% of patients (Table S2). Among patients where treatment was restarted, the keratopathy had improved to at least a grade 2. Emergent keratopathy was seen in 75% (n = 9) of patients on re-introduction of treatment. The other adverse effects noted in our series include hematological toxicity (n = 9), abnormal liver enzymes (n = 1) and anaphylaxis (n = 1). The overall response rates were 44.6% (n = 25) with ≥ very good partial remission (VGPR) rates of 21% (n = 12) for the entire cohort. Median progression free survival (PFS) and OS for the entire cohort was 3.6 months and 10 months respectively (Figure S1). We then compared PFS and OS for patients that held Belantamab due to keratopathy and subsequently restarted after the keratopathy improved (n = 16) and those that discontinued because of continued keratopathy or due to patient preference (n = 13). We show that PFS is significantly improved for patients who restarted Belantamab therapy (10 months vs. 4 months, p = .032, Figure S2A), while the median OS in both groups was not reached (Figure S2B, NS). We then looked at only at patients who achieved at least a VGPR and then held therapy due to keratopathy and saw a trend for improved PFS in patients that restarted (n = 11, median PFS = 7.6 months) compared to those who continued to hold Belantamab (n = 6, median PFS = 4.1 months), albeit the patient numbers were small for this analysis and the results were not significant (p = .16, data not shown). Taken together, our data suggests that a substantial number of patients with keratopathy come off therapy despite having disease control, which leads to reduced PFS. Among the 12 patients who remain on belantamab, the ORR was 83.3% (n = 10) with ≥VGPR rate of 42% (n = 5) and the remainder with SD. All of these 12 patients were being maintained with a reduced dose schedule of 1.9 mg/kg at every 6–12 weeks. Keratopathy, albeit still present with a grade II in most patients (9/12), appeared to be more tolerable. Taken together, while our study was limited by retrospective analysis, small sample size and failure to capture patient reported ocular symptoms, it is the largest series of RRMM patients treated with belantamab in a real-world setting. More than 70% of patients developed either new or worsening of pre-existing keratopathy within 4 months of belantamab therapy with grade 3 accounting for 54% of the events. Keratopathy led to treatment interruption in 48% of patients by month 4 of belantamab therapy. Overall, treatment was permanently discontinued due to ocular toxicity in 25% (n = 14/56) patients, despite having at least a PR, and PFS in those patients was significantly worse compared to those, who restarted Belantamab therapy, suggesting that the occurrence of keratopathy and associated subjective symptoms have a major impact on treatment outcome. In the pivotal DREAMM2 study grade 3 keratopathy accounted for a third of the cases in contrast to more than half of the cases in our report. In addition, while corneal toxicity leading to permanently discontinuation was rare (1%) in the DREAMM 2 study,10 this was higher in our series accounting for 25% of cases. Furthermore, in a single institution experience of belantamab therapy, corneal keratopathy was noted only in 43% of patients, mostly consisting of grade 1–2 events. The ORR rate in this study was 33% with median PFS was 2 months and median OS of 6.5 months.12 The discrepancies between these studies and ours in terms of keratopathy is not quite clear, but could be due the exclusion of patients with corneal epithelial disease except for mild punctate keratopathy5 in the DREAMM 2 study, whereas a third of patient in our study had grade 1 keratopathy going into belantamab therapy. A recent analysis of US claims data showed that ocular co-morbidities are found in 40% of newly diagnosed MM and the prevalence increases with the number of lines of therapy in RRMM.11 Furthermore, it is possible that the current keratopathy grading system (Table S3) needs to be optimized or alternative grading systems need to be explored. This is of importance as patients that are able to manage or tolerate their keratopathy and that respond to belantamab can have long-term disease control. A small case series of patients with a long follow up of 32.6 month reports PFS ranging from 18-NR months despite the several dose interruptions and reductions due to incident corneal toxicity.13 Similarly, in our cohort, 21% (12/56) of patients were able to stay on belentamab with reduced dose and dosing schedule with a median follow up time of 7.4 months. Albeit keratopathy was still present, it was more tolerable and the ongoing responses in these patients suggest that the belantamab can be safely reduced without losing efficacy. Several ongoing trials are investigating different treatment dosing and frequency schedules to optimize the risk–benefit profile.14 In conclusion, belantamab has shown significant single agent efficacy in pretreated, heavily relapsed patients. Improving the ocular toxicity will further improve the efficacy as patients will be more willing to continue the treatment. Work completed by CS was funded the National Institutes of Health (Grant No. P20GM109005). The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.